This proposal is concerned with the fate of insulin secreted or injected into non-immune and insulin-immunized subjects, guinea pigs and rabbits being used as experimental models. In non-immune species it is postulated that insulin concentrations observed in peripheral blood are influenced not only by the rate at which insulin is secreted, but also by the rate at which the hormone is taken up and metabolized by the liver, kidneys and other tissues. The isolated perfused liver and isolated hepatocytes will be used to study hepatic metabolism of insulin and the effects of hormones, drugs, metabolites and other factors upon this process. In immune subjects it is postulated that insulin is metabolized abnormally, the reticulo-endothelial system and other immunological phenomena playing the dominant role. Using insulin- immunized guinea pigs and rabbits as experimental models, the fate of injected insulin will be studied in acute experiments, to determine the part played by the reticulo-endothelial system and the effects of drugs which might influence phagocytosis; and in chronic experiments, to determine whether insulin-antibody complexes are deposited on the basement membranes of small blood-vessels to cause micro-vascular lesions. The results obtained with such experimental models may be of value in determining the factors which cause insulin resistance and microangiopathy in insulin-treated diabetics, and so suggest methods for their prevention or treatment.